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negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell. [GOC:obol]

Negative regulation of T cell activation via T cell receptor (TCR) contact with antigen bound to MHC molecule on antigen presenting cell (APC) is a critical process that prevents excessive immune responses and maintains immune homeostasis. It involves a complex interplay of signaling pathways and regulatory molecules, ensuring that T cells are only activated when necessary and avoiding autoimmune reactions.

Here's a detailed breakdown of the process:

1. **Antigen Presentation:** APCs, such as dendritic cells, macrophages, and B cells, engulf antigens and process them into small peptides. These peptides are then displayed on the cell surface bound to MHC molecules (MHC I for CD8+ T cells and MHC II for CD4+ T cells).
2. **TCR Recognition:** The TCR on the surface of T cells recognizes and binds to the specific antigen-MHC complex. This interaction triggers the activation of the TCR signaling cascade.
3. **Signal Transduction:** TCR engagement initiates a series of signaling events involving various intracellular molecules, including tyrosine kinases (Lck, Fyn), the ζ chain of the TCR complex, and downstream signaling molecules like ZAP70 and PLCγ1.
4. **Calcium Signaling:** Activation of PLCγ1 leads to the hydrolysis of phosphatidylinositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 triggers the release of calcium ions (Ca2+) from intracellular stores, leading to increased intracellular calcium levels.
5. **Activation of Transcription Factors:** The rise in intracellular calcium activates calcineurin, a phosphatase that dephosphorylates the transcription factor NFAT (nuclear factor of activated T cells). De-phosphorylated NFAT translocates to the nucleus, where it interacts with other transcription factors, such as AP-1 and NF-κB, to initiate gene expression.
6. **Negative Regulatory Mechanisms:**
* **CTLA-4 and PD-1:** These inhibitory receptors are expressed on activated T cells. They bind to their ligands (CD80/CD86 for CTLA-4 and PD-L1/PD-L2 for PD-1) on APCs. This interaction triggers inhibitory signaling pathways, leading to downregulation of TCR signaling and suppression of T cell activation.
* **Phosphatases:** Several phosphatases, including SHP-1 and SHP-2, dephosphorylate key signaling molecules involved in TCR activation, thus terminating the signaling cascade.
* **Apoptosis:** In the absence of sufficient costimulatory signals, activated T cells can undergo apoptosis (programmed cell death), preventing excessive immune responses.
* **Treg Cells:** Regulatory T cells (Tregs) play a crucial role in suppressing T cell activation. They express high levels of CTLA-4 and other inhibitory molecules and secrete immunosuppressive cytokines like IL-10 and TGF-β.

The intricate balance between positive and negative regulatory mechanisms ensures that T cell activation is tightly controlled, preventing autoimmune reactions and maintaining immune tolerance. These negative regulatory mechanisms are essential for preventing excessive immune responses and maintaining immune homeostasis.'
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Proteins (2)

ProteinDefinitionTaxonomy
Hepatitis A virus cellular receptor 2A hepatitis A virus cellular receptor 2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8TDQ0]Homo sapiens (human)
Galectin-3A galectin-3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P17931]Homo sapiens (human)

Compounds (10)

CompoundDefinitionClassesRoles
lactosebeta-lactose : The beta-anomer of lactose.

lactose : A glycosylglucose disaccharide, found most notably in milk, that consists of D-galactose and D-glucose fragments bonded through a beta-1->4 glycosidic linkage. The glucose fragment can be in either the alpha- or beta-pyranose form, whereas the galactose fragment can only have the beta-pyranose form.

Lactose: A disaccharide of GLUCOSE and GALACTOSE in human and cow milk. It is used in pharmacy for tablets, in medicine as a nutrient, and in industry.
lactose
methyl alpha-d-galactopyranosidemethyl alpha-D-galactoside : An alpha-D-galactoside having a methyl substituent at the anomeric position.

methyl-galactopyranoside: structure in first source
alpha-D-galactoside;
methyl D-galactoside;
monosaccharide derivative
methyl beta-galactosidemethyl beta-D-galactoside : A beta-D-galactopyranoside having a methyl substituent at the anomeric position.

methyl beta-galactoside: RN given refers to (beta-D)-isomer

methyl galactoside : A methyl glycoside in which the H of the OH group on C-1 of galactose is replaced by a methyl group.
beta-D-galactoside;
methyl D-galactoside;
monosaccharide derivative
thiodigalactosidethiodigalactoside: RN given refers to beta-D-galactopyranoside (D-Gal)-isomer
methyl lactosidebeta-D-Gal-(1->4)-beta-D-Glc-OMe : A methyl glycoside comprising methyl beta-D-glucoside having an beta-D-galactosyl residue at the 4-position.disaccharide derivative;
methyl glycoside
n-acetyllactosamineN-acetyllactosamine : A beta-D-galactopyranosyl-(1->4)-N-acetyl-D-glucosamine having beta-configuration at the reducing end anomeric centre.

N-acetyllactosamine: RN given refers to D-isomer
beta-D-Galp-(1->4)-D-GlcpNAc
galactosealpha-D-galactoside : Any D-galactoside having alpha-configuration at its anomeric centre.D-galactopyranosemouse metabolite
5-chloro-1h-benzimidazole-2-thiol5-chloro-1H-benzimidazole-2-thiol: trypanocidal
galactalgalactal: RN given refers to cpd with unspecified isomeric designation; structureanhydrohexose;
glycal
pf-2545920